Psychostimulant abuse and addiction are causes of intense suffering for the individual and represent a major public health concern. Yet, few therapies exist to treat these devastating conditions. Psychostimulants like cocaine and amphetamine hijack dopamine (DA) reward pathways, leading to elevated synaptic DA. Emerging data implicate the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) in modulating components of these drug reward circuitries. GLP-1, a hormone and neuropeptide, is released by L-cells of the intestines in response to food intake and acts through both peripheral and central mechanisms to regulate energy homeostasis and feeding behaviors. It has been shown that activation of mesolimbic GLP-1Rs decreases the intake of highly palatable foods, suggesting that GLP-1R signaling regulates the hedonic components of food intake and possibly reward processes. We have recently discovered that systemic administration of a long- lasting GLP-1 analogue (exendin-4 or Ex-4), attenuates the rewarding effects of cocaine in mice. Ex-4 also reduces amphetamine-induced locomotor activity in rats. Importantly, GLP-1Rs are expressed within the hypothalamus, ventral tegmental area (VTA), and nucleus accumbens, but are especially enriched in the lateral septum (LS). The LS is known to receive dopaminergic input from the VTA, an important area in psychostimulant abuse, but little is known about the modulation of DA neurotransmission in this area. In the present study, we will test the overarching hypothesis that GLP-1R activation modulates DA neurotransmission and signaling within the LS. Importantly, we hypothesize that this regulation blunts the rewarding effects of psychostimulants. To determine functional modulation of DA neurotransmission in the LS, we will first measure effects of GLP-1R stimulation on DA uptake and clearance, as well as on trafficking of presynaptic DA transporter (DAT) and DA D2 receptors, molecular targets of psychostimulants (Aim 1). Next, we will evaluate whether local GLP-1R signaling within the LS mediates the therapeutic effects of systemic Ex-4 on cocaine reward (Aim 2). Finally, we propose to determine the cellular phenotype of GLP- 1-activated neurons in the LS in relation to DA innervation and DA receptor expression patterns (Aim 3). These experiments will determine the role of GLP-1 signaling in regulating the rewarding properties of psychostimulants. Because this study takes a mechanistic approach, its findings have the potential to various reward dysfunctions, including drug reward and food reward. Notably, GLP-1 long-lasting analogues are already FDA-approved and on the market for the treatment of diabetes; thus these findings may be readily translatable to the treatment of psychostimulant drug abuse.